In a joint study with investigators in Laboratory of Molecular Biology, NCI and Institut National de la Recherche Agronomique (INRA), France, we are attacking the problem of protein structure classification, with the goal of improving automated methods for recognizing and classifying protein domains in three dimensional structures. Domains are thought to be the building blocks of complex structures, and often determine protein function. We have recently shown that two distinct structure similarity measures (VAST and SHEBA) can obtain at best about 75-80% agreement with a standard manually curated protein classification (SCOP), calling into question the existence of sharp boundaries between protein "folds". We have published a further analysis of "C-class" or alpha/beta protein domains, by hierarchically clustering domains based on measured structural similarity by three different methods (VAST, SHEBA and DALI). We found that automatic classifications differ little from each other, relative to their overall differences from SCOP. One implication is that identification of conserved motifs or cores may be necessary before identifying domain classes. We have developed three related algorithms for defining domains based on recurrence of similar domains in other structural contexts in other proteins in the PDB. Starting with a list of similar fragments to the query structure, the algorithms determine whether to divide the query into one or multiple domains, and the domain boundaries. Some domains appear to be discontinuous within the structure, indicating a possible evolutionary insertion of the underlying DNA sequence corresponding to the inserted domain. Testing and validation of these algorithms is currently underway. With an investigator in the Division of International Epidemiology and Population Studies, Fogarty International Center, we have developed a phenomenological model of Plasmodium/red blood cell dynamics moderated by host immune and erythropoietic responses. All stages of the parasite's intra-host lifecycle are incorporated in the model, along with plausible human immune responses. An invited talk describing previous results of this work was presented the 2009 SIAM Conference on Dynamical Systems. We are studying how regulation of parasitmia by both host and parasite factors affects transmissibility of the parasite to its mosquito vector;in particular, we are studying the difference in transmission strategies between the different Plasmodium species which cause human disease. Working with experimental investigators in the Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, we are studying the population biology of Plasmodium parasites within their mosquito vectors, particularly, the spread of genes in the parasite population which might affect the adaptability of the parasite to new carriers. With investigators in the Section on Medical Biophysics, Laboratory of Integrative Biophysics, National Institute of Child Health and Human Development, and with the Signal Processing and Instrumentation Section, Computational Bioscience and Engineering Laboratory, Division of Computational Bioscience, Center for Information Technology, we are working on model of the thermal and fluid transport processes that occur in the operation of expression microdissection (xMD), a method of extracting large number of cells of specific types from a tissue sample. Because of a new NIH-wide initiative to expand applications of the xMD, the current modeling focuses on new configurations of the xMD device. In 2008 results of some of this work were presented at the 2008 Meeting of the Biomedical Society. With investigators with the National Cancer Institute and CIC BioGune (a non-profit laboratory in Bilbao, Spain), investigated the physical topology of gene transcription. This work is a continuation of a project that started when the Spanish investigator was a post-doctorial fellow here at NIH. During 2009 a paper discussing the result that the mRNA from the gene which expresses Zac1 protein was preferentially close to the nucleolus, even though mRNA form other transcribing genes of similar spatial distribution in nuclei were not, was published in Chromosoma. With investigators in the Section on Medical Biophysics, Laboratory of Integrative Biophysics, NICHD, and with the Signal Processing and Instrumentation Section, Computational Bioscience and Engineering Laboratory, Division of Computational Bioscience, Center for Information Technology, we are working of a model of the thermal and fluid transport processes that occur in the operation of expression microdissection (xMD), a newly developed method of extraction large number of cells from a tissue sample. xMD shows great promise, but a better theoretical understanding of its operations is needed before it can commercially developed or be fully exploited in an NIH core facility. In a project with investigators of NIMH, we analyzed multiple-electrode recordings from in-vitro neural network preparations in order to deduce the underlying cortical network topology. We developed a new algorithm for network reconstruction from the observed avalanche dynamics in multiple electrode neuronal recordings. Applying this algorithm to the multiple-electrode recordings from in-vitro neural network preparations we revealed a novel property of these networks which show robust clustering properties upon removal of the weak links. Simulations indicate that such network architecture results when the link weights are correlated with the clustering coefficients of the respective end nodes. A manuscript describing this work is in preparation. In a continuing project with investigators in the Laboratory of Integrative and Medical Biophysics (LIMB), NICHD we conduct a theoretical study of the observed skewed and heavy-tailed distribution of the axonal diameters. We show that the observed distribution can arise when optimizing the information transfer through axonal bundles. A book chapter titled "Statistical Issues in DT-MRI" describing the work done in collaboration with this group will appear in "Diffusion MRI: Theory, Methods and Applications" late in 2009. In another project with LIMB, NICHD, related to the development of the optical imaging techniques we derived theoretical predictions for the effects of the photon-fluorophore interactions in the time-gated optical imaging techniques. A software tool written in Python (Fluorofit) implements this model and enables efficient estimation of the relevant biological parameters. This software tool has been made available to our collaborators.